Method of intra-articular administration and its use

Abstract

This application provides a method for preventing or treating periarthritis of a prosthesis (PJI), or a method for alleviating PJI-related symptoms. The method comprises administering a therapeutic agent into the joint of a patient in need, the therapeutic agent comprising a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof. TIFF2026520113000009.tif77170

Description

[Technical Field]

[0001] This application relates to the biomedical field, and more specifically to a method for preventing or treating diseases by intra-articular administration. [Background technology]

[0002] Artificial joint replacement surgery is a procedure that replaces joints that are painful and unable to function normally due to arthritis, joint disease, osteoarthritis, rheumatoid arthritis, etc., with artificial joints, and is widely used as an effective treatment in clinical practice. Periarthritis of the joint (prosthetic joint infection, PJI) is a serious complication after total hip arthroplasty (THA) or total knee arthroplasty (TKA), and can result from complete surgical failure, causing joint dysfunction in the affected limb, and in severe cases, leading to amputation or death. The etiology of PJI is mainly related to biofilm infection, with incidence rates of 0.5% to 1.2% and 0.5% to 1.6%, respectively, and the number of PJI patients is increasing along with the increase in the number of patients undergoing joint replacement surgery. Currently, PJI is usually managed with a combination of surgery and antibiotic therapy. Surgical treatment often requires the physical destruction or removal of biofilms through surgical debridement, but preventing reinfection is difficult, the long-term prognosis after treatment is poor, and it causes significant suffering to patients. Antibiotic therapy also faces the challenge of drug resistance and multidrug resistance in infecting bacteria. Due to the complex pathology and extreme difficulty in treating PJI, patients often require multiple reoperations and long-term systematic antibiotic therapy, severely impacting their quality of life due to repeated hospitalizations and prolonged mobility difficulties, and medical costs can be several times, sometimes tens of times, higher than for patients without PJI. Furthermore, while antibiotic use is essential regardless of the PJI treatment regimen, unified implementation standards and research results regarding the timing, optimal duration and dosage, and route of administration of antibiotics in PJI treatment have not yet been established in the medical community. Many clinical application protocols are based on expert consensus and experience, so there is an urgent need for high-quality, reliably effective (non-surgical) antibiotic therapy in this field. [Overview of the project]

[0003] This invention provides a more practical and effective treatment method to overcome the shortcomings of conventional techniques in the treatment of periarthritis of artificial joints.

[0004] In one embodiment, the present invention provides a method for preventing or treating periarthritis of a prosthesis (PJI), or a method for alleviating PJI-related symptoms. The method comprises administering a therapeutic agent into the joint of a patient in need, the therapeutic agent comprising a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof. TIFF2026520113000002.tif77170

[0005] In some embodiments, this method involves administering the therapeutic agent into the joint of the patient in need at a dosage frequency selected from once a day, once every two days, once every three days, once every four days, once every five days, once every six days, and once every seven days.

[0006] In some embodiments, the method involves administering the therapeutic agent into the joint of the patient in need over a period of 1 day to approximately 6 months, during which the frequency of administration of the therapeutic agent is the same or varied.

[0007] In some embodiments, the therapeutic agent is administered to patients in need by one or more intra-articular injections in a single dose.

[0008] In some embodiments, the therapeutic agent contains approximately 10 mg to approximately 300 mg of the compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof in a single dose.

[0009] In some embodiments, the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers.

[0010] In some embodiments, the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are not mixed with each other.

[0011] In some embodiments, one or more other components are mixed with a compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof.

[0012] In some embodiments, this method further includes administering an effective amount of another therapeutic agent to the patient in need.

[0013] In some embodiments, periprosthetic joint infection (PJI) is caused by Gram-positive bacterial infection.

[0014] In some embodiments, periprosthetic joint infection (PJI) is caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcal infection.

[0015] In some embodiments, periarthritis of the prosthesis (PJI) includes early PJI, acute hematogenous PJI, and chronic PJI.

[0016] In some embodiments, periarthritis of the joint (PJI) is either an early PJI that occurs within approximately three months of the patient undergoing artificial joint replacement surgery, or an acute hematogenous PJI that occurs within approximately four weeks post-surgery.

[0017] In some embodiments, the patients requiring treatment include those who have not yet developed peri-prosthetic joint infection (PJI) but are at risk of developing PJI.

[0018] In some embodiments, this method involves administering a therapeutic agent into the target joint over a period of 1 to 14 days.

[0019] In some embodiments, the first day of the 1-14 day period is the day the subject undergoes artificial joint replacement surgery.

[0020] According to another aspect, the present application provides the use of a compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride in the manufacture of a therapeutic agent. This therapeutic agent is used to prevent or treat periprosthetic joint infection (PJI) or to relieve PJI-related symptoms and is formulated for intra-articular administration to a patient in need thereof.

[0021] In some embodiments, the therapeutic agent is formulated for administration into the joint of a patient in need thereof at an administration frequency selected from once a day, once every two days, once every three days, once every four days, once every five days, once every six days, and once every seven days.

[0022] In some embodiments, the therapeutic agent is formulated for administration into the joint of a patient in need thereof over a period of one day to about six months, and over the period of one day to about six months, the therapeutic agent is formulated for administration to the patient in need thereof at the same or different administration frequencies.

[0023] In some embodiments, the therapeutic agent is formulated for one or more intra-articular injections in a single administration.

[0024] In some embodiments, the therapeutic agent contains from about 10 mg to about 300 mg of the compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride in a single administration.

[0025] In some embodiments, the therapeutic agent further contains other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers.

[0026] In some embodiments, the other components and the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride are not mixed with each other.

[0027] In some embodiments, one or more other components are mixed with a compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof.

[0028] In some embodiments, the therapeutic agent is formulated to be administered in combination with an effective amount of another therapeutic agent to patients who require it.

[0029] In some embodiments, periprosthetic joint infection (PJI) is caused by Gram-positive bacterial infection.

[0030] In some embodiments, periprosthetic joint infection (PJI) is caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcal infection.

[0031] In some embodiments, periarthritis of the prosthesis (PJI) includes early PJI, acute hematogenous PJI, and chronic PJI.

[0032] In some embodiments, periarthritis of the joint (PJI) is either an early PJI that occurs within approximately three months of the patient undergoing artificial joint replacement surgery, or an acute hematogenous PJI that occurs within approximately four weeks post-surgery.

[0033] In some embodiments, the patients requiring treatment include those who have not yet developed peri-prosthetic joint infection (PJI) but are at risk of developing PJI.

[0034] In some embodiments, the therapeutic agent is formulated to be administered intra-articular over a period of 1 to 14 days.

[0035] In some embodiments, the first day of the 1-14 day period is the day the subject undergoes artificial joint replacement surgery.

[0036] The specific features of the invention described herein are set forth in the attached claims. The features and advantages of the invention described herein can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows. [Brief explanation of the drawing]

[0037] [Figure 1A-1B] This figure shows the number of colonies in metal implants and bone joints in mice administered the treatment regimen of the present invention and other treatment regimens. The horizontal axis, from left to right, represents the high-dose, medium-dose, and low-dose groups of compound IA of formula (I), the high-dose, medium-dose, and low-dose groups of compound IP of formula (I), the vancomycin IA group, the solvent control group, the blank group infected for 14 days, and the blank group infected for 7 days. [Figure 2A-2B] This figure shows (A) the state of artificial joints implanted in rats after administration of the treatment regimen of the present invention and other treatment regimens, as observed with an electron microscope, and (B) the pathological H&E staining results of the synovial tissue of the rats. [Figure 3] This figure shows the drug concentration-time curves in plasma and synovial fluid samples of the compound of formula (I) after administering the treatment regimen of the present invention to male and female beagle dogs. [Modes for carrying out the invention]

[0038] The embodiments of the present invention will be described below with reference to specific examples. Those skilled in the art will readily understand other advantages and effects of the present invention from the information disclosed herein.

[0039] Definition of Terms In this application, the term “patients in need” may generally include human patients and other mammalian subjects receiving prophylactic or therapeutic treatment (including, but not limited to, non-human primates, experimental animals such as rabbits, dogs, rats, and mice, and other animals). These “patients in need” may, for example, be subjects with a confirmed specific disease, subjects receiving treatment related to a specific disease, or subjects with a tendency or risk of developing a specific disease.

[0040] In this application, the term "subject at risk" generally refers to an observed or treated person who is at high probability of developing a particular disease or condition based on some risk factor. For example, in this application, risk factors include, but are not limited to, a lack of resistance to a particular infectious disease or infectious illness, having been in, being in, or being in an environment that is infectious. In some embodiments, this type of subject may be asymptomatic or exhibit symptoms that have not been formally diagnosed.

[0041] In this application, the term “administration” usually refers to introducing a drug or a drug-containing composition into a patient’s body via any introduction or delivery route. Any method known to those skilled in the art may be employed to bring cells, organs, or tissues into contact with the drug or its composition. The term “single dose” may be divided into one or more appropriate doses to be administered once or more times within a given period.

[0042] In this application, the term "therapeutic agent" usually refers to a compound, mixture of compounds, composition, biopolymer, or extract made from a biomaterial that, when administered appropriately to a patient, can induce a desired therapeutic effect, prevent the onset of a disease, or alleviate a related disease.

[0043] In this application, the term "pharmaceutically acceptable salt" usually refers to conventional acid-addition salts or base-addition salts that retain the biological efficacy and properties of a parent compound, such as the compound represented by formula (I). Examples of acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, and trifluoroacetic acid. Base-addition salts include those derived from inorganic bases such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts, and those derived from organic bases such as primary amines, secondary amines, and tertiary amines. Chemical modification of (pharmaceutical) compounds into salts is a well-known technique among medicinal chemists to improve the physical and chemical stability, hygroscopicity, fluidity, and solubility of compounds. For example, see Ansel, H., et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., 1995.

[0044] In this application, the terms "solvated compound" and "solvate" are interchangeable and generally refer to an association or complex of one or more solvent molecules with the salt-type compound of this application. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" generally refers to a complex in which the solvent molecule is water.

[0045] In this application, the term "prodrug" usually refers to a substance that, when administered to a patient, can be metabolized to form a compound having the structure of the compound of this application. The term "metabolite" usually refers to a substance obtained by metabolism when the compound of this application is administered to a patient. Prodrugs and metabolites contained in these derivatives are included within the scope of the present invention.

[0046] In this application, the terms "deuteride" and "deuterated compound" are interchangeable and generally refer to new compounds in which one or more hydrogen atoms in an organic compound are replaced by deuterium atoms.

[0047] In this application, the term “drug” usually refers to a molecule having the desired biological efficacy. Drugs may be prophylactic or therapeutic. Drugs may include, but are not limited to, protein molecules including peptides, polypeptides, proteins (post-translational modified proteins, fusion proteins, antibodies, etc.), small molecules including inorganic or organic compounds, double-stranded or single-stranded DNA, double-stranded or single-stranded RNA (antisense(molecules), RNAi, etc.), intron sequences, triple-stranded nucleic acid molecules, nucleic acid molecules including aptamers, or vaccines (e.g., Lister vaccines and non-Lister vaccines). Drugs may be obtained from known organisms (including, but not limited to, animals, plants, bacteria, fungi, protozoa, viruses, etc.) or synthetic molecule libraries.

[0048] In this application, the term “pharmaceutically acceptable carrier” usually refers to one or more non-toxic substances that do not interfere with the efficacy of the biological activity of the active ingredient. Such formulations may typically include salts, buffers, preservatives, compatible carriers, and, if necessary, other therapeutic agents. Such pharmaceutically acceptable formulations may also include compatible solid or liquid fillers, diluents, or encapsulating materials suitable for administration to humans. Other carriers, excipients, and / or additives that can be used in the formulations described herein include, for example, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids, protein excipients (such as serum albumin, gelatin, and casein), and salt-forming ions (such as sodium). These and other known drug carriers, excipients, and / or additives suitable for use in the formulations described herein are well known in the art and are listed, for example, in "Remington: The Science & Practice of Pharmacy," 21st edition, Lippincott Williams & Wilkins (2005) and "Physician's Desk Reference," 60th edition, Medical Economics, Montvale, New Jersey (2005). A suitable pharmaceutically acceptable carrier can be determined by routinely selecting the desired or required method of administration, solubility, and / or stability.

[0049] In this application, the term “mixing” usually refers to the process of combining one or more compounds, cells, molecules, etc., into a single unit within the same area. This can be done, for example, in a test tube, a Petri dish, or any container that allows for the mixing of one or more compounds, cells, or molecules.

[0050] In this application, the term "occurs" usually refers to a patient or subject exhibiting clinical symptoms associated with a particular disease. For example, in this application, this may refer to clinical symptoms associated with early, acute, or chronic periprosthetic joint infection.

[0051] In this application, the term "including" generally means including the explicitly specified features but not excluding other elements. The terms "greater than or equal to" and "less than or equal to" generally mean including a reference numerical value.

[0052] In this application, the term "selected from" generally refers to the selected subjects and all combinations thereof. For example, "(:) selected from A, B, and C" means all combinations of A, B, and C, such as A, B, C, A+B, A+C, B+C, or A+B+C.

[0053] In this application, the terms “effective dose” or “effective amount” are interchangeable and generally refer to an amount sufficient to achieve, or at least partially achieve, the desired therapeutic effect. When used in patients who require it, it generally refers to an amount sufficient to cure, or at least partially prevent, the disease and its complications in patients who already have it. The effective dose for this use depends on the severity of the patient’s infection and the overall state of the patient’s immune system.

[0054] In this application, the term "combined administration" generally refers to the administration of the therapeutic agent described herein together with other therapeutic agents or drugs, either as a single formulation or as multiple independent formulations. Combined administration can be performed simultaneously or sequentially in any order, and is preferably performed, for example, over a period of time during which two (or all) active ingredients exert biological activity simultaneously. The therapeutic agent described herein and other therapeutic agents do not necessarily have to be administered via the same route of administration.

[0055] In this application, the terms “about” or “approximately” usually refer to being within the tolerance range of a particular value as determined by those skilled in the art, and this depends in part on how the value is measured or determined, i.e., the limits of the measuring system. For example, “about” or “approximately” may mean within or exceeding one standard deviation, according to the convention of the art. Alternatively, “about” or “approximately” may mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg may include any number between 2.7 mg and 3.3 mg (in the case of 10%) or between 2.4 mg and 3.6 mg (in the case of 20%). Furthermore, particularly with respect to biological systems or processes, this term may mean a value of up to one order of magnitude or a value of up to five times. Where specific values ​​or compositions are given in this specification and the appended claims, unless otherwise specified, the meaning of “about” or “approximately” should be assumed to be within the tolerance range of that specific value or composition.

[0056] Details of the invention In one embodiment, the present invention provides a method for treating periarthritis of a prosthesis (PJI). This method may include administering a therapeutic agent into the joint of a patient in need, the therapeutic agent may include a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof.

[0057] In some embodiments, this method may include administering the therapeutic agent into the joint of the patient in need at a frequency of administration selected from once a day, once every two days, once every three days, once every four days, once every five days, once every six days, and once every seven days.

[0058] In some embodiments, this method may include administering the therapeutic agent into the joint of the patient in need over a period of 1 day to approximately 6 months, and the frequency of administration of the therapeutic agent may be the same or varied over a period of 1 day to approximately 6 months. For example, this method may include administering the agent on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (1 month), 31, 32, 33, 34, 35, 36, 37, 38, 39 This may include administering the therapeutic agent into the joints of patients as needed over a period of 1, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 days (2 months), approximately 3 months, approximately 4 months, approximately 5 months, or approximately 6 months. During the period of therapeutic agent administration, the frequency of administration may be maintained at the same frequency or may be changed according to the actual needs of the patient or the doctor's instructions.

[0059] In some embodiments, the therapeutic agent is administered to patients in need by one or more intra-articular injections in a single administration. For example, the therapeutic agent is administered intra-articularly to patients in need by one, two, three, four, five, or six or more bolus injections in a single administration. Here, the two or more bolus injections may be administered consecutively or at the same or different time intervals. The therapeutic agent administered by two or more bolus injections may contain the compound represented by formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterated compounds in equal or different amounts.

[0060] In some embodiments, the therapeutic agent contains approximately 10 mg to approximately 300 mg of the compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof in a single dose. For example, the amount of compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated contained in a single dose of the therapeutic agent may be about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg.

[0061] In some embodiments, the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers. For example, the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are not mixed with each other. For example, “not mixed with each other” may mean that the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are each housed in separate containers and / or devices. For example, “not mixed with each other” may mean that the container or device housing the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides in the therapeutic agent and the container or device housing the other components are each housed in separate storage spaces and / or under different storage conditions. For example, “not to be mixed” may mean that the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are dispensed and stored in specific units in their respective containers and / or devices. For example, “not to be mixed” may mean that the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are mixed only before use of the therapeutic agent. This mixing process may include, using a mixing device included in or not included in the therapeutic agent, transferring and mixing other components with the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride into a container or device containing another component, and / or transferring other components with the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride into another container or device.

[0062] In some embodiments, the therapeutic agent comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers, one or more of the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are mixed with each other. For example, “mixed with each other” may mean that one or more of the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are mixed and contained in the same container or device. For example, “mixed with each other” may mean that one or more of the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides, after being mixed, are dispensed and stored in specific units in the same or different containers or devices. For example, “to be mixed with each other” may mean that one or more of the other components and the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride need to be further thoroughly mixed (e.g., shaken vigorously to thoroughly mix) before use of the therapeutic agent after they have been mixed.

[0063] In some embodiments, this method further includes administering an effective amount of another therapeutic agent to a patient in need. For example, this method further includes administering an effective amount of another therapeutic agent to a patient by injection (primarily via non-articular routes, e.g., intravenous, intramuscular, and / or subcutaneous injection), oral administration, intracavitary (excluding intra-articular) administration, enteral administration, and / or transdermal absorption. For example, the other therapeutic agent may be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormonal agents, anti-inflammatory agents, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeabilizers, and muscle relaxants.

[0064] Periprosthetic joint infections (PIAs) can be caused by a wide range of pathogens, including a single pathogen or multiple pathogens. In some embodiments, PIAs can be caused by Gram-positive bacterial infections. For example, PIAs can be caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcal infection. Specifically, coagulase-negative staphylococci may be selected from Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus xylosus, Staphylococcus haemolyticus, Staphylococcus capitis, Staphylococcus warneri, Staphylococcus simulans, Staphylococcus xylosus, and Staphylococcus simiae. In this application, Gram-positive bacteria may further include drug-resistant strains, for example, drug-resistant strains that are resistant to rifamycin (e.g., rifampicin) alone, quinolones or quinolidinones alone, or both rifamycin and quinolidinones. For example, drug-resistant strains may be resistant to macrolides such as clarithromycin, azithromycin, and roxithromycin; nitroimidazoles such as metronidazole, ornidazole, pretomanid, and delamanid; aminoglycosides such as streptomycin and amikacin; β-lactams such as methicillin, ampicillin, and amoxicillin; tetracyclines such as tetracycline, tigecycline, and minocycline; oxazolidinones such as linezolid and tedizolid; nitrofurans such as furazolidone; polypeptides such as vancomycin and polymyxin; diarylquinolines such as bedaquiline; and other antibiotics such as clofazimine. In this application, the diagnosis of whether a patient has periarthritis of the prosthesis can be made by combining known diagnostic methods and criteria in the art with the patient's detailed medical history, physical examination, serological tests, microbiological tests, pathological tests, and imaging results.

[0065] In some embodiments, periarthritis of the prosthesis (PJI) includes early PJI, acute hematogenous PJI, and chronic PJI. Because the symptoms and pathogenesis of PJI are complex and diverse, a unified standard for the diagnosis and classification of PJI has not yet been established in this field. However, based on the clinical characteristics and timing of infection, commonly used classification methods include the Tsukayama method (Tsukayama DT, Estrada R, Gustilo RB. Infection after total hip arthroplasty. A study of the treatment of 106 infections [J]. J Bone Joint Surg Am, 1996, 78(4):512-523; and Tsukayama DT, Goldberg VM, Ky le R. Diagnostics and management of infection after total knee arthroplasty [J]. J Bone Joint Surg Am, 2003, 85A(1):75-80.) and the Zimmerli method (Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections [J]. N Engl J Examples include the Coventry method (Coventry MB. Treatment of infections occurring in total hip surgery. Orthop Clin North Am 1975;6:991-1003.), the Barrett method (Barrett L, Atkins B. The clinical presentation of prosthetic joint infection. J Antimicrob Chemother. 2014 Sep;69 Suppl1:i25-7.). For example, Zimmerli et al. define PJI occurring within 3 months after total hip replacement surgery as early PJI infection, PJI occurring between 3 and 24 months post-surgery as delayed or mid-stage PJI infection, and PJI occurring 24 months or more post-surgery as late-stage infection.For example, periarthritis of the artificial joint may be acute hematogenous PJI that occurs within approximately four weeks after surgery.

[0066] In some embodiments, the patients requiring treatment may include those who have not yet developed periarthritis of the joint (PJI) but are at risk of developing PJI. For example, this method may include administering the therapeutic agent into the joint of the subject over a period of 1 to 14 days. Specifically, this method may include administering the therapeutic agent into the joint of the subject over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, and the frequency of administration of the therapeutic agent may be maintained at the same frequency during the administration period, or may be changed according to the actual needs of the subject or according to the physician's instructions. For example, the first day of the 1 to 14-day period is the day the subject undergoes artificial joint replacement surgery. In this application, it is possible to determine whether there is a risk of developing PJI based on the subject's detailed medical history, physical examination, diagnostic report, treatment plan, etc.

[0067] In another aspect, the present application provides the use of a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof in the manufacture of a therapeutic agent. This therapeutic agent is used to treat periarthritis of prostheses and is formulated for intraarticular administration to patients in need.

[0068] In some embodiments, the therapeutic agent is formulated to be administered intra-articularly to patients in need at a frequency of administration selected from once daily, once every two days, once every three days, once every four days, once every five days, once every six days, and once every seven days.

[0069] In some embodiments, the therapeutic agent is formulated to be administered intra-articularly to patients in need over a period of 1 day to approximately 6 months, and over a period of 1 day to approximately 6 months, the therapeutic agent is formulated to be administered to patients in need at the same or different dosing frequencies. For example, the therapeutic agent may be administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (1 month), 31, 32, 33, 34, 35, 36, 37, 38, 39 The drug may be formulated to be administered intra-articularly to patients who need it over any number of days selected from 1 day, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 ​​days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days (2 months), approximately 3 months, approximately 4 months, approximately 5 months, or approximately 6 months. During the period of administration, the therapeutic agent may be formulated to maintain the same frequency of administration, or to be administered to patients who need it at different frequencies, according to the actual needs of the patient or as directed by the physician.

[0070] In some embodiments, the therapeutic agent is formulated to be suitable for one or more intra-articular injections in a single administration. For example, the therapeutic agent is formulated to be administered intra-articularly to a patient in need by one, two, three, four, five, or six or more bolus injections in a single administration. Here, two or more bolus injections may be carried out by formulating the therapeutic agent to be administered as consecutive bolus injections, or by formulating the therapeutic agent to be administered as bolus injections at the same or different time intervals. The therapeutic agent administered by two or more bolus injections may contain equal or different amounts of the compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride.

[0071] In some embodiments, the therapeutic agent contains approximately 10 mg to approximately 300 mg of the compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof in a single dose. For example, the amount of compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated contained in a single dose of the therapeutic agent may be about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg.

[0072] In some embodiments, the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers. For example, the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are not mixed with each other. For example, “not mixed with each other” may mean that the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are each housed in separate containers and / or devices. For example, “not mixed with each other” may mean that the container or device housing the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides in the therapeutic agent and the container or device housing the other components are each housed in separate storage spaces and / or under different storage conditions. For example, “not to be mixed” may mean that the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are dispensed and stored in specific units in their respective containers and / or devices. For example, “not to be mixed” may mean that the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are mixed only before use of the therapeutic agent. This mixing process may include, using a mixing device included in or not included in the therapeutic agent, transferring the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride to a container or device containing another component and mixing them, or transferring the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride to a separate container or device and mixing them.

[0073] In some embodiments, the therapeutic agent comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers, one or more of the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are mixed with each other. For example, “mixed with each other” may mean that one or more of the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides are mixed and contained in the same container or device. For example, “mixed with each other” may mean that one or more of the other components and the compound of formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides, after being mixed, are dispensed and stored in specific units in the same or different containers or devices. For example, “to be mixed with each other” may mean that one or more of the other components and the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride need to be further thoroughly mixed (e.g., shaken vigorously to thoroughly mix) before use of the therapeutic agent after they have been mixed.

[0074] In some embodiments, the therapeutic agent is formulated to be administered concomitantly to patients in need, in an effective amount of another therapeutic agent. For example, the therapeutic agent may be formulated to be administered concomitantly to patients in need, in an effective amount of another therapeutic agent, the other therapeutic agent may be administered to the patient by injection (mainly via non-articular routes, e.g., intravenous, intramuscular, and / or subcutaneous injection), oral administration, intracavitary (excluding intra-articular) administration, enteral administration, and / or transdermal absorption. For example, the other therapeutic agent may be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormonal agents, anti-inflammatory agents, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeabilizers, and muscle relaxants.

[0075] In some embodiments, periarthritis of the joint (PJI) is caused by Gram-positive bacterial infection. For example, periarthritis of the joint may be caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcus infection. Specifically, the coagulase-negative staphylococci may be selected from Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus xylosus, Staphylococcus haemolyticus, Staphylococcus capitis, Staphylococcus warneri, Staphylococcus simulans, Staphylococcus xylosus, and Staphylococcus simiae. In this application, Gram-positive bacteria may further include drug-resistant strains, for example, drug-resistant strains that are resistant to rifamycin (e.g., rifampicin) alone, quinolones or quinolidinones alone, or both rifamycin and quinolidinones. For example, drug-resistant strains may be resistant to macrolides such as clarithromycin, azithromycin, and roxithromycin; nitroimidazoles such as metronidazole, ornidazole, pretomanid, and delamanid; aminoglycosides such as streptomycin and amikacin; β-lactams such as methicillin, ampicillin, and amoxicillin; tetracyclines such as tetracycline, tigecycline, and minocycline; oxazolidinones such as linezolid and tedizolid; nitrofurans such as furazolidone; polypeptides such as vancomycin and polymyxin; diarylquinolines such as bedaquiline; and other antibiotics such as clofazimine. In this application, the diagnosis of whether a patient in need has periarthritis of the prosthesis can be made by combining known diagnostic methods and criteria in the art with the patient's detailed medical history, physical examination, serological tests, microbiological tests, pathological tests, and imaging results.

[0076] In some embodiments, periarthritis of the joint (PJI) includes early PJI, acute hematogenous PJI, and chronic PJI. For example, PJI occurring within 3 months after artificial joint replacement surgery is defined as early PJI infection, PJI occurring between 3 and 24 months post-surgery is defined as delayed or mid-stage PJI infection, and PJI occurring 24 months or more post-surgery is defined as late-stage infection (Zimmerli et al., 2004). For example, periarthritis of the joint may be acute hematogenous PJI occurring within approximately 4 weeks post-surgery.

[0077] In some embodiments, the patients requiring treatment may include those who have not yet developed periarthritis of the joint (PJI) but are at risk of developing PJI. For example, the therapeutic agent may be formulated to be administered into the joint of the subject over a period of 1 to 14 days. Specifically, the therapeutic agent may be formulated to be administered into the joint of the subject over any number of days selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. During the administration period, the therapeutic agent may be formulated to maintain the same administration frequency, or to be administered into the joint of the subject at different frequencies as required by the patient or as directed by the physician. For example, the first day of the 1 to 14-day period is the day the subject undergoes artificial joint replacement surgery. In this application, the risk of developing PJI can be determined based on the subject's detailed medical history, physical examination, diagnostic report, treatment plan, etc.

[0078] While not limited by any theory, the following examples are merely for illustrative purposes to illustrate the method and use of the present invention and do not limit the scope of the present invention. [Examples]

[0079] Example 1 Evaluation of the efficacy of the present invention's treatment method in a mouse model. 1. Experimental Method In this study, female mice aged 8-10 weeks were randomly assigned to groups. Before the start of treatment, each mouse underwent surgery to insert a metal implant into the femorotibial joint, and was inoculated with methicillin-sensitive Staphylococcus aureus (MSSA, strain ATCC6538) into the joint at the surgical site.

[0080] The preparation of the therapeutic agent is as follows: (1) Compound of formula (I): For therapeutic agents for intra-articular injection (IA), the compound is dissolved in a 5% glucose aqueous solution (D5W) to prepare the desired concentration. For therapeutic agents for intraperitoneal injection (IP), the compound is dissolved in an ethanol / NaHCO3 / 6% cremaphor solvent system to prepare the desired concentration. (2) Vancomycin: Dissolve in sterile water for injection (WFI) to prepare the desired concentration to obtain a therapeutic agent for intra-articular injection.

[0081] The experimental design for evaluating the therapeutic effect is as follows: TIFF2026520113000003.tif117170

[0082] 2.Result analysis Samples were collected from the surgical and inoculation sites of mice, and the number of colonies on agar plates was measured and converted to CFU / tissue colony-forming units. The specific conversion method involved multiplying the number of colonies by the amount of homogenate in the spot and the dilution factor of the calculated number of colonies (5-50 colonies / spot), and then log the resulting value. 10 The data was expressed as CFU / organization, and the mean and standard deviation were calculated (the results are shown in Table 1).

[0083] TIFF2026520113000004.tif117170

[0084] Table 1 and Figures 1A-1B show that on day 7 of treatment, the average number of colonies in the metal implant and femur was 5.35 log, respectively. 10 CFU and 6.77log 10 This indicates that it was a CFU (Congenital Fibreous Untreated). On day 14, the mean number of colonies in the metal implants and femur of untreated control animals was 4.77 log, respectively.10 CFU and 6.88log 10 It was CFU.

[0085] Intra-articular administration of the compound of formula (I) resulted in an average colony count of 2.5–2.72 log higher in the metal implant and femur compared to untreated control animals. 10 CFU, 1.71~3.42log 10 CFU decreased. Compared to the control group, the results for all formula (I) compound IA dose groups were judged to be statistically significant (P<0.0001). Compared to the vancomycin IA dose group, the number of colonies in metal implants in the 45 mg / kg, 15 mg / kg, and 5 mg / kg formula (I) compound IA dose groups, and the number of colonies in the femur in the 45 mg / kg and 15 mg / kg formula (I) compound IA dose groups were judged to be statistically significant (P<0.0001). Compared to the intra-articular (IP) administration (BID) route of compound (I), the 45 mg / kg dose showed similar therapeutic effects. However, the number of femoral colonies in the 15 mg / kg and 5 mg / kg IA dose groups (QD) of compound (I) was statistically significant (P<0.0001) compared to the IP administration of the same dose of compound (I). Similarly, the number of implant colonies in the 15 mg / kg IA dose group and the 15 mg / kg IP dose group of compound (I) were also statistically significant (P<0.0001). Furthermore, intra-articular administration is advantageous for improving patient compliance due to its lower administration frequency.

[0086] Example 2 Evaluation of the efficacy of the present invention's treatment method in a rat PJI model. 1. Experimental Method In this study, rats approximately 17 weeks old were used. Before the start of treatment, each rat underwent aseptic surgery to insert and replace an artificial knee joint, and then methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300 strain) was inoculated into the joint at the surgical site.

[0087] Furthermore, the details of each experimental group and its experimental content are designed as follows. TIFF2026520113000005.tif100170

[0088] 2. Result analysis In this example, when measuring the MIC values (minimum growth inhibitory concentration) of vancomycin and the compound of formula (I) against MRSA ATCC 43300 strain, MIC バンコマイシン was 0.5 μg / mL, and MIC 式(I) was 0.032 μg / mL, indicating that the compound of formula (I) has a stronger bactericidal effect than vancomycin in vitro. From the results of the electron microscope shown in Figure 2A, in the control infection group (solvent group), a large number of colonies and biofilms were formed on the artificial joint. In the low-dose group of the compound of formula (I), many colonies were still observed, and the bacteria were surrounded by many microproteins. In the medium-dose group, the microproteins were distributed in a network pattern, some were concentrated and bundled, and some bacteria remained. In the high-dose group, the microproteins were evenly distributed, and some cocci were scattered. In the vancomycin group, a large number of bacteria still remained, and the microproteins were distributed in a network pattern. The above results indicate that for the bacteria colonized on the artificial joint, the medium-dose and high-dose groups of the compound of formula (I) have a stronger ability to inhibit the growth of bacteria and biofilms than the vancomycin group.

[0089] From the H&E staining results of the synovium and soft tissues shown in Figure 2B, severe stromal cell proliferation, an increase in the number of cell layers, and inflammatory cell infiltration were observed in the synovium of the control infection group. On the other hand, in the vancomycin group and the low-dose, medium-dose, and high-dose groups of the compound of formula (I), the synovitis symptoms showed varying degrees of improvement. In the high-dose group of the compound of formula (I) and the vancomycin group, the inflammatory cell infiltration in the synovium significantly decreased, and the synovitis symptoms significantly alleviated.

[0090] Table 2 shows the sampling and CFU values ​​(viable bacterial count) statistics for prosthesis (primary evaluation site for PJI infection), bone tissue (primary evaluation site for PJI infection), and soft tissue (non-primary evaluation site for PJI infection) after treatment for each group. The results of the efficacy experiment showed that, compared to the solvent control group, the low-dose, medium-dose, and high-dose groups of compound (I) all showed good bactericidal effects. Compared to the vancomycin group, the low-dose, medium-dose, and high-dose groups of compound (I) showed excellent bactericidal effects in both prosthesis and bone tissue, while the medium-dose and high-dose groups of compound (I) showed considerable bactericidal effects in soft tissue.

[0091] TIFF2026520113000006.tif76170

[0092] Summary: In this example, a stable rat prosthesis infection model was constructed using S. aureus ATCC43300, and the antibacterial activity of the compound of formula (I) in injection solution within the joint was evaluated. As a result, intra-articular administration of the compound of formula (I) effectively reduced the number of viable bacteria in the rat joint, exhibiting dose-dependent bactericidal activity. Compared to the vancomycin group, the medium-dose and high-dose groups showed stronger bactericidal activity.

[0093] Example 3 Pharmacokinetic analysis of the therapeutic method of this invention in male and female beagle dogs In this example, animal model experiments were conducted using male and female beagle dogs to evaluate the pharmacokinetic behavior of the compound of formula (I) after a single injection into the knee joint. Six beagle dogs (3 males and 3 females) were selected for this experiment. The experimental animals received a single injection of 3 mg / kg of the compound of formula (I) into the left knee joint and a single injection of 0.1 mL / kg of the solvent (5% glucose injection) into the right knee joint. Plasma samples were collected from the experimental animals before administration (0 hours), and at 0.25 (15 minutes), 3, 9, 12, 24, 36, 48, and 72 hours after administration. Synovial fluid samples were collected from the left knee at 12, 36, and 60 hours after administration. The concentrations of the compound of formula (I) in the plasma and synovial fluid samples were measured using high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0094] TIFF2026520113000007.tif89170

[0095] According to the experimental results shown in Table 3, after the above injection was administered into the joints of Beagle dogs, the highest concentration of compound (I) in plasma and synovial fluid (C max The MICs were 736±247 ng / mL and 77400±81900 ng / mL, respectively, against Staphylococcus aureus (15 ng / mL) and Staphylococcus epidermidis (8 ng / mL). 90 The value was significantly higher than expected. The concentration in synovial fluid was related to the biofilm bactericidal activity of MBBC against Staphylococcus aureus and epidermal fungi. 90 The values ​​were significantly higher than those of 2000 ng / mL and 250 ng / mL. Furthermore, high exposure levels were observed in both plasma and synovial fluid, and AUC 0-last The values ​​were 20800±7150 ng·h / mL and 1000000±1050000 ng·h / mL, respectively, for the AUC of synovial fluid and plasma. 0-last The ratio was 46.1, indicating that the drug was concentrated in the synovial fluid of the joint, which is expected to reduce clinical side effects due to high systemic exposure.

Claims

1. A method for preventing or treating periarthritis of a prosthesis (PJI), or a method for alleviating PJI-related symptoms, the method comprising administering a therapeutic agent into the joint of a patient in need, wherein the therapeutic agent comprises a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof.

2. The method according to claim 1, comprising administering the therapeutic agent into the joint of the patient in need at a frequency of administration selected from once a day, once every two days, once every three days, once every four days, once every five days, once every six days, and once every seven days.

3. The method according to any one of claims 1 to 2, comprising administering the therapeutic agent into the joint of the patient in need over a period of one day to approximately six months, wherein the frequency of administration of the therapeutic agent during the period of one day to approximately six months is the same or modified.

4. The method according to any one of claims 1 to 3, wherein the therapeutic agent comprises about 10 mg to about 300 mg of a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof in a single dose.

5. The method according to any one of claims 1 to 4, wherein the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers.

6. The method according to claim 5, wherein the other components and the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride are not mixed with each other.

7. The method according to claim 5, wherein one or more of the other components are mixed with the compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof.

8. The method according to any one of claims 1 to 7, further comprising administering an effective amount of another therapeutic agent to the patient in need.

9. The method according to any one of claims 1 to 8, wherein the periarthritis of the artificial joint (PJI) is caused by a Gram-positive bacterial infection.

10. The method according to any one of claims 1 to 9, wherein the periarthritis of the artificial joint (PJI) is caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcus infection.

11. The method according to any one of claims 1 to 10, wherein the periarthritis of a prosthesis (PJI) includes early PJI, acute hematogenous PJI, and chronic PJI.

12. The method according to any one of claims 1 to 11, wherein the periarthritis of the artificial joint (PJI) is an early PJI occurring within approximately three months after the patient requiring the procedure undergoes artificial joint replacement surgery, or an acute hematogenous PJI occurring within approximately four weeks after the replacement surgery.

13. The method according to any one of claims 1 to 12, wherein the patients requiring the treatment include those who have not yet developed the periarthritis of the prosthesis (PJI) but are at risk of developing the PJI.

14. The method according to claim 13, comprising administering the therapeutic agent into the target joint over a period of 1 to 14 days.

15. The method according to claim 14, wherein the first day of the period from day 1 to day 14 is the day on which the subject undergoes artificial joint replacement surgery.

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